Alkynyl-substituted quinolin-2-one derivatives useful as anticancer agents

ABSTRACT

The present invention relates to compounds of formula 1and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are as defined herein. The above compounds of formula 1 are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering the compounds of formula 1 to a mammal requiring such treatment

This is a division of application Ser. No. 09/628,039, filed Jul. 27,2000, which is a division of application Ser. No. 09/383,755, filed Aug.26, 1999, now U.S. Pat. No. 6,150,377, issued Nov. 21, 2000, whichclaims the benefit of U.S. Provisional Application No. 60/098,145, filedAug. 27, 1998, now abandoned, all of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

This invention relates to a series of alkynyl-substituted quinolin-2-onederivatives that are useful in the treatment of hyperproliferativediseases, such as cancers, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer.

To acquire transforming potential, the precursor of the Ras oncoproteinmust undergo farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzesthis modification, farnesyl protein transferase, have therefore beensuggested as agents to combat tumors in which Ras contributes totransformation. Mutated, oncogenic forms of Ras are frequently found inmany human cancers, most notably in more than 50% of colon andpancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837,1993). The compounds of the present invention exhibit activity asinhibitors of the enzyme farnesyl protein transferase and are thereforebelieved to be useful as anticancer and anti-tumor agents. Further, thecompounds of the present invention may be active against any tumors thatproliferate by virtue of farnesyl protein transferase.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula 1

and to pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

the dashed line indicates that the bond between C-3 and C-4 of thequinolin-2one ring is a single or double bond;

R¹ is selected from H, C₁-C₁₀ alkyl, —(CR¹³R¹⁴)_(q)C(O)R¹²,—(CR¹³R¹⁴)_(q)C(O)OR¹⁵, —(CR¹³R¹⁴)_(q)OR¹², —(CR¹³R¹⁴)_(q)SO₂R¹⁵,—(CR¹³R¹⁴)_(t)(C₃-C₁₀ cycloalkyl), —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), and—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl andheterocyclic R₁ groups are optionally fused to a C₆-C₁₀ aryl group, aC₅-C₈ saturated cyclic group, or a 4-10 membered heterocyclic group; andthe foregoing R¹ groups, except H but including any optional fused ringsreferred to above, are optionally substituted by 1 to 4 R⁶ groups;

R² is halo, cyano, —C(O)OR¹⁵, or a group selected from the substituentsprovided in the definition of R¹²;

each R³, R⁴, R⁵, R⁶, and R⁷ is independently selected from H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, halo, cyano, nitro, mercapto, trifluoromethyl,trifluoromethoxy, azido, —OR¹², —C(O)R¹², —C(O)OR¹², —NR¹³C(O)OR¹⁵,—OC(O)R¹², —NR¹³SO₂R¹⁵, —SO₂NR¹²R¹³, —NR¹³C(O)R₁₂, —C(O)NR¹²R¹³,—NR¹²R¹³, —CH═NOR¹², —S(O)_(j)R¹² wherein j is an integer from 0 to 2,—(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), —(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic),—(CR¹³R¹⁴)_(t)(C₃-C₁₀ cycloalkyl), and —(CR¹³R¹⁴)_(t)C≡CR¹⁵, and whereinin the foregoing R³, R⁴, R⁵, R⁶, and R⁷ groups t is an integer from 0 to5; the cycloalkyl, aryl and heterocyclic moieties of the foregoinggroups are optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturatedcyclic group, or a 4-10 membered heterocyclic group; and said alkyl,alkenyl, cycloalkyl, aryl and heterocyclic groups are optionallysubstituted by 1 to 3 substituents independently selected from halo,cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR¹³SO₂R¹⁵,—SO₂NR¹²R¹³, —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —NR¹³C(O)OR¹⁵,—NR¹³C(O)R¹², —C(O)NR¹²R¹³, —NR¹²R¹³, —OR¹², C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), and—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5;

R⁸ is H, —OR¹², —NR¹²R¹³, —NR¹²C(O)R¹³, cyano, —C(O)OR¹³, —SR¹²,—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5, or C₁-C₆ alkyl, wherein said heterocyclic and alkyl moieties areoptionally substituted by 1 to 3 R⁶ substituents;

R⁹ is —(CR¹³R¹⁴)_(t)(imidazolyl) wherein t is an integer from 0 to 5 andsaid imidazolyl moiety is optionally substituted by 1 or 2 R⁶substituents;

each R¹⁰ and R¹¹ is independently selected from the substituentsprovided in the definition of R⁶;

each R¹² is independently selected from H, C₁-C₁₀ alkyl,—(CR¹³R¹⁴)_(t)(C₃-C₁₀ cycloalkyl), —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), and—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5; said cycloalkyl, aryl and heterocyclic R¹² groups are optionallyfused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclic group, or a 4-10membered heterocyclic group; and the foregoing R¹² substituents, exceptH, are optionally substituted by 1 to 3 substituents independentlyselected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,azido, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —NR¹³C(O)R¹⁴, —C(O)NR¹³R¹⁴,—NR¹³R¹⁴, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

each R¹³ and R¹⁴ is independently H or C₁-C₆ alkyl, and where R¹³ andR¹⁴ are as —(CR¹³R¹⁴)_(q) or (CR¹³R¹⁴)_(t) each is independently definedfor each iteration of q or t in excess of 1;

R¹⁵ is selected from the substituents provided in the definition of R¹²except R¹⁵ is not H;

R¹⁶ is selected from the list of substituents provided in the definitionof R¹² and —SiR¹⁷R¹⁸R¹⁹;

R¹⁷, R¹⁸ and R¹⁹ are each independently selected from the substituentsprovided in the definition of R¹² except R¹⁷, R¹⁸ and R¹⁹ are not H; and

provided that at least one of R³, R⁴ and R⁵ is —(CR¹³R¹⁴)_(t)C≡CR¹⁶wherein t is an integer from 0 to 5 and R¹³, R¹⁴, and R¹⁶ are as definedabove.

Preferred compounds of formula 1 include those wherein R¹ is H, C₁-C₆alkyl, or cyclopropylmethyl; R² is H; R³ is —C≡CR¹⁶; and R⁸ is —NR¹²R¹³,—OR¹², or a heterocyclic group selected from triazolyl, imidazolyl,pyrazolyl, and piperidinyl, wherein said heterocyclic group isoptionally substituted by an R⁶ group. More preferred compounds includethose wherein R⁹ is imidazolyl optionally substituted by C₁-C₆ alkyl; R⁸is hydroxy, amino, or triazolyl; and R⁴, R⁵, R¹⁰ and R¹¹ are eachindependently selected from H and halo.

Other preferred compounds formula 1 include those wherein R¹ is—(CR¹³R¹⁴)_(t)(C₃-C₁₀ cycloalkyl) wherein t is an integer from 0 to 3;R² is H; R³ is —C≡CR¹⁶; and R⁸ is —NR¹²R¹³, —OR¹², or a heterocyclicgroup selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl,wherein said heterocyclic group is optionally substituted by an R⁶group. More preferred compounds include those wherein R⁹ is imidazolyloptionally substituted by C₁-C₆ alkyl; R⁸ is hydroxy, amino, ortriazolyl; R⁴, R⁵, R¹⁰ and R¹¹ are each independently selected from Hand halo; and R¹ is cyclopropylmethyl.

Other preferred compounds formula 1 include those wherein R³ is ethynyland the other substituents are as defined above.

Specific preferred compounds include the following:

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(enantiomer A);

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(enantiomer B);

6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(enantiomer A);

6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(enantiomer B);

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-4-fluoro-phenyl)-1-methyl-1H-quinolin-2one;

and the pharmaceutically acceptable salts, prodrugs and solvates of theforegoing compounds, as well as stereoisomers of the foregoingcompounds.

The present invention also relates to intermediates of formula 28

wherein R¹, R², R³, R₄, R⁵, R⁶, R⁷, R¹⁰ and R¹¹ are as defined above.

The present invention also relates to the following specificintermediates which may be used in the preparation of the compounds ofthe present invention

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2one

6-(4-Chloro-benzoyl)-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

6-(4-Chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-one

6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one.

The present invention also relates to a method of preparing a compoundof formula 1 wherein R³ is ethynyl, which comprises treating a compoundof formula 29

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined abovewith tetrabutylammonium fluoride.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, prodrug or solvate thereof, thatis effective in inhibiting farnesyl protein transferase. In oneembodiment of this method, the abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said method, said abnormalcell growth is a benign proliferative disease, including, but notlimited to, psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, prodrug or solvate thereof, thatis effective in treating abnormal cell growth.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal atherapeutically effective amount of a compound of formula 1, or apharmaceutically acceptable salt, prodrug or solvate thereof, incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, and anti-androgens.

The present invention also relates to a method for the treatment of aninfection in a mammal, including a human, that is facilitated byfarnesyl protein transferase, such as hepatitus delta virus or malaria,which comprises administering to said mammal a therapeutically effectiveamount of a compound of formula 1 or a pharmaceutically acceptable salt,prodrug or solvate thereof.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, prodrug or solvate thereof, thatis effective in inhibiting farnesyl protein transferase, and apharmaceutically acceptable carrier. In one embodiment of saidcomposition, said abnormal cell growth is cancer, including, but notlimited to, lung cancer, bone cancer, pancreatic cancer, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, uterine cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'sDisease, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, prostate cancer, chronic oracute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer ofthe kidney or ureter, renal cell carcinoma, carcinoma of the renalpelvis, neoplasms of the central nervous system (CNS), primary CNSlymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, prodrug or solvate thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier.

The invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises a therapeutically effective amount of a compound of formula 1,as defined above, or a pharmaceutically acceptable salt, prodrug orsolvate thereof, in combination with a pharmaceutically acceptablecarrier and an anti-tumor agent selected from the group consisting ofmitotic inhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,and anti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of an infection in a mammal, including a human, that isfacilitated by farnesyl protein transferase, such as malaria orhepatitus delta virus, comprising an amount of a compound of the formula1, as defined above, or a pharmaceutically acceptable salt, prodrug orsolvate thereof, that is effective in treating abnormal cell growth, anda pharmaceutically acceptable carrier.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) expressing an activated Rasoncogene; (2) tumor cells in which the Ras protein is activated as aresult of oncogenic mutation in another gene; (3) benign and malignantcells of other proliferative diseases in which aberrant Ras activationoccurs; and (4) any tumors that proliferate by virtue of farnesylprotein transferase.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties.

The term “cycloalkyl”, as used herein, unless otherwise indicated,includes cyclic alkyl moieties wherein alkyl is as defined above.

The term “alkenyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above.

The term “alkynyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein alkyl is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one or more heteroatoms, generally 1 to 4 heteroatoms, eachselected from O, S and N, wherein each heterocyclic group has from 4-10atoms in its ring system. Non-aromatic heterocyclic groups includegroups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems and ring systemssubstituted with one or more oxo moieties. An example of a 4 memberedheterocyclic group is azetidinyl (derived from azetidine). An example ofa 5 membered heterocyclic group is thiazolyl and an example of a 10membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groupsare pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. The foregoing groups, as derived fromthe compounds listed above, may be C-attached or N-attached where suchis possible. For instance, a group derived from pyrrole may bepyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).

Where R¹³ and R¹⁴ are as (CR¹³R¹⁴)_(q) or (CR¹³R¹⁴)_(t) each isindependently defined for each iteration of q or t in excess of 1. Thismeans, for instance, that where q or t is 2 alkylene moieties of thetype —CH₂CH(CH₃)—, and other asymmetrically branched groups, areincluded.

The term “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups that maybe present in the compounds of formula 1. For example, pharmaceuticallyacceptable salts include sodium, calcium and potassium salts ofcarboxylic acid groups and hydrochloride salts of amino groups. Otherpharmaceutically acceptable salts of amino groups are hydrobromide,sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate,methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. Thepreparation of such salts is described below.

The subject invention also includes isotopically-labelled compounds, andthe pharmaceutically acceptable salts thereof, which are identical tothose recited in formula 1, but for the fact that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S,¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention,prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingand methods of treating bacterial infections through administeringprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of formula 1. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. The amideand ester moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B.H. Stewart, Advanced Drug Delivery Reviews (1996)19, 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acylgroup may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in R. P. Robinson et al., J. Medicinal Chemistry (1996) 39,10.

Certain compounds of formula 1 may have asymmetric centers and thereforeexist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of formula 1, and mixtures thereof, areconsidered to be within the scope of the invention. With respect to thecompounds of formula 1, the invention includes the use of a racemate,one or more enantiomeric forms, one or more diastereomeric forms, ormixtures thereof. In particular, the carbon to which the R⁸ and R⁹groups are attached represents a potential chiral center; the presentinvention encompasses all stereoisomers based on this chiral center. Thecompounds of formula 1 may also exist as tautomers. This inventionrelates to the use of all such tautomers and mixtures thereof. Certaincompounds of formula 1 may also include oxime moieties, such as whereR³, R⁴, R⁵, R⁶ or R⁷ is —CH═NOR¹², that exist in E or Z configurations.The present invention includes racemic mixtures of compounds of formula1 that include such oxime moieties or specific E or Z isomers of suchcompounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula 1 may be prepared as described below.

With reference to Scheme 1 below, the compounds of formula 1 may beprepared by hydrolysing an intermediate ether of formula 2, wherein R isC₁-C₆ alkyl, according to methods familiar to those skilled in the art,such as by stirring the intermediate of formula 2 in an aqueous acidsolution. An appropriate acid is, for example, hydrochloric acid. Theresulting quinolinone of formula 1 wherein R¹ is hydrogen may betransformed into a quinolinone wherein R¹ has a meaning as defined aboveapart from hydrogen by N-alkylation methods familiar to those skilled inthe art.

With reference to Scheme 2 below, the compounds of formula 1(b), whichare compounds of formula 1 wherein R⁸ is hydroxy, may be prepared byreacting an intermediate ketone of formula 3 with an intermediate of theformula H—R⁹, wherein R⁹ is as defined above and wherein in theimidazolyl moiety of said R⁹ group a free nitrogen atom may be protectedwith an optional protective group, such as a sulfonyl group (forexample, a dimethylamino sulfonyl group) which can be removed after theaddition reaction. Said reaction requires the presence of a suitablestrong base, such as sec-butyl lithium, in an appropriate solvent, suchas tetrahydrofuran, and the presence of an appropriate silanederivative, such as chloro-tert-butyldimethylsilane. The silyl group canbe removed with a fluoride source such as tetrabutyl ammonium fluoride.Other procedures with protective groups analogous to silane derivativescan also be applied.

With reference to Scheme 3 below, compounds of formula 1(b-1), which arecompounds of formula 1 wherein the dotted line is a bond and R¹ ishydrogen, can be prepared by reacting an intermediate of formula 21 withan intermediate of formula H—R⁹, wherein R⁹ is as described above. Theresulting intermediate of formula 22 undergoes ring opening of theisoxazole moiety by stirring it with an acid, such as TiCl₃, in thepresence of water. Subsequent treatment of the resulting intermediate offormula 23 with a suitable reagent, such as R²CH₂COCl or R²CH₂COOC₂H₅,wherein R² is as defined above, yields either directly a compound offormula 1(b-1) or an intermediate which can be converted to a compoundof formula 1(b-1) by treatment with a base, such as potassiumtert-butoxide.

Intermediates of formula 21 can be prepared by treating an intermediateof formula 16, referred to below with respect to Scheme 9, under acidicconditions.

With reference to Scheme 4 below, compounds of formula 1 wherein R⁸ is aradical of formula —NR¹²R¹³ wherein R¹² and R¹³ are as described above(said compounds are represented below by formula 1(g)), may be preparedby reacting an intermediate of formula 13, wherein W is an appropriateleaving group, such as halo, with a reagent of formula 14. Said reactionmay be performed by stirring the reactants in an appropriate solvent,such as tetrahydrofuran.

Compounds of formula 1(g), or other embodiments of formula 1, whereinthe dotted line represents a bond can be converted into compoundswherein the dotted line does not represent a bond by hydrogenationmethods familiar to those skilled in the art. Compounds wherein thedotted line does not represent a bond may be converted into compoundswherein the dotted line represents a bond by oxidation methods familiarto those skilled in the art.

With reference to Scheme 5 below, compounds of formula 1 wherein R⁸ ishydroxy (said compounds being represented by formula 1(b)) may beconverted into compounds of formula 1(c), wherein R¹² has the meaningdescribed above except it is not hydrogen, by methods known to thoseskilled in the art, including O-alkylation or O-acylation reactions;such as by reacting the compound of formula 1(b) with an alkylatingreagent such as R¹²—W, wherein R¹² is as described above, in appropriateconditions, such as in a dipolar aprotic solvent, such as DMF, in thepresence of a base, such as sodium hydride. W is a suitable leavinggroup, such as a halo group or a sulfonyl group.

As an alternative to the above reaction procedure, compounds of formula1(c) may also be prepared by reacting a compound of formula 1(b) with areagent of formula R¹²—OH, wherein R¹² is as described above, in acidicmedium.

Compounds of formula 1(b) may also be converted into compounds offormula 1(g), wherein R¹² is hydrogen and R¹³ is replaced with C₁-C₆alkylcarbonyl, by reacting compounds of formula 1(b) in acidic medium,such as sulfuric acid, with C₁-C₆ alkyl-CN in a Ritter-type reaction.Further, compounds of formula 1(b) may also be converted into compoundsof formula 1(g), wherein R¹² and R¹³ are hydrogen, by reacting acompound of formula 1(b) with ammonium acetate and subsequent treatmentwith NH₃(aq.).

With reference to Scheme 6 below, compounds of formula 1(b), referred toabove, may also be converted into compounds of formula 1(d), wherein R⁸is hydrogen, by submitting a compound of formula 1(b) to appropriatereducing conditions, such as stirring in trifluoroacetic acid in thepresence of an appropriate reducing agent, such as sodium borohydride,or, alternatively, stirring the compound of formula 1(b) in acetic acidin the presence of formamide. Further, the compound of formula 1(d)wherein R⁸ is hydrogen may be converted into a compound of formula 1(e)wherein R¹² is C₁-C₁₀ alkyl by reacting the compound of formula 1(d)with a reagent of formula 5, wherein W is an appropriate leaving group,in an appropriate solvent, such as diglyme, in the presence of a base,such as potassium tert-butoxide.

With reference to Scheme 7 below, compounds of formula 1 may be preparedby reacting a nitrone of formula 6 with the anhydride of a carboxylicacid, such as acetic anhydride, thus forming the corresponding ester onthe 2-position of the quinoline moiety. Said quinoline ester can behydrolyzed in situ to the corresponding quinolinone using a base, suchas potassium carbonate.

Alternatively, compounds of formula 1 can be prepared by reacting anitrone of formula 6 with a sulfonyl containing electrophilic reagent,such as p-toluenesulfonylchloride, in the presence of a base, such asaqueous potassium carbonate. The reaction initially involves theformation of a 2-hydroxy-quinoline derivative which is subsequentlytautomerized to the desired quinolinone derivative. The application ofconditions of phase transfer catalysis, which are familiar to thoseskilled in the art, may enhance the rate of the reaction.

Compounds of formula 1 may also be prepared by an intramolecularphotochemical rearrangement of compounds of formula 6, referred toabove. Said rearrangement can be carried out by dissolving the reagentsin a reaction-inert solvent and irradiating at a wavelength of 366 nm.It is advantageous to use degassed solutions and to conduct the reactionunder an inert atmosphere, such as oxygen-free argon or nitrogen gas, inorder to minimize undesired side reactions or reduction of quantumyield.

The substituents of the compounds of formula 1 may be converted to othersubstituents falling within the scope of formula 1 via reactions orfunctional group transformations familiar to those skilled in the art. Anumber of such transformations are already described above. Otherexamples are hydrolysis of carboxylic esters to the correspondingcarboxylic acid or alcohol; hydrolysis of amides to the correspondingcarboxylic acids or amines; hydrolysis of nitrites to the correspondingamides; amino groups on imidazole or phenyl moieties may be replaced byhydrogen by diazotation reactions familiar to those skilled in the art,and subsequent replacement of the diazo-group by hydrogen; alcohols maybe converted into esters and ethers; primary amines may be convertedinto secondary or tertiary amines; double bonds may be hydrogenated tothe corresponding single bond.

With reference to Scheme 8 below, intermediates of formula 3, referredto above, may be prepared by reacting a quinolinone derivative offormula 8 with an intermediate of formula 9, or a functional derivativethereof, under appropriate conditions, such as in the presence of astrong acid (for example, polyphosphoric acid) in an appropriatesolvent. The intermediate of formula 8 may be formed by cyclization ofan intermediate of formula 7 by stirring in the presence of a strongacid, such as polyphosphoric acid. Optionally, said cyclization reactionmay be followed by an oxidation step, which can be performed by stirringthe intermediate formed after cyclization in an appropriate solvent,such as a halogenated aromatic solvent (for example, bromobenzene), inthe presence of an oxidizing agent, such as bromine or iodine. At thisstage, the R¹ substituent may be changed to a different moiety by afunctional group transformation reaction familiar to those skilled inthe art.

With reference to Scheme 9 below, intermediates of formula 3(a-1), whichare intermediates of formula 3 wherein the dotted line is a bond and R¹and R² are hydrogen, can be prepared starting from an intermediate offormula 17, which is conveniently prepared by protecting thecorresponding ketone. Said intermediate of formula 17 is stirred with anintermediate of formula 18 in the presence of a base, such as sodiumhydroxide, in an appropriate solvent, such as an alcohol (for example,methanol). The resulting intermediate of formula 16 will undergohydrolysis of the ketal and ring opening of the isoxazole moiety bystirring the intermediate of formula 16 with an acid, such as TiCl₃, inthe presence of water. Subsequently, acetic anhydride can be used toprepare an intermediate of formula 15, which will undergo ring closurein the presence of a base, such as potassium tert-butoxide.

Intermediates of formula 3(a-1) can be converted to intermediates offormula 3(a), which are intermediates of formula 3 wherein the dottedline represents a bond, R² is hydrogen, and R¹ is other than hydrogen asdefined above, using N-alkylation procedures familiar to those skilledin the art.

With reference to Scheme 10 below, an alternative method of preparingintermediates of formula 3(a-1), wherein R¹ is hydrogen, begins with anintermediate of formula 16 which can be converted to an intermediate offormula 19 using catalytic hydrogenation conditions, such as by usinghydrogen gas and palladium on carbon in a reaction-inert, solvent suchas tetrahydrofuran (THF). The intermediates of formula 19 can beconverted into an intermediate of formula 20 by submitting theintermediate of formula 19 to an acetylation reaction, such as bytreatment with the anhydride of a carboxylic acid (for example, aceticanhydride) in a reaction-inert solvent, such as toluene, and subsequenttreatment with a base, such as potassium tert-butoxide, in areaction-inert solvent, such as 1,2-dimethoxyethane. The intermediate offormula 3(a-1) can be obtained by subjecting the intermediate of formula20 to acidic conditions.

With reference to Scheme 11 below, the intermediate of formula 2,referred to above, may be prepared by reacting an intermediate offormula 10, wherein W is an appropriate leaving group, such as halo,with an intermediate ketone of formula 11. This reaction is done byconverting the intermediate of formula 10 into a organometalliccompound, by stirring it with a strong base such as butyl lithium, andsubsequently adding the intermediate ketone of formula 11. Although thisreaction gives at first instance a hydroxy derivative (R⁸ is hydroxy),said hydroxy derivative can be converted into other intermediateswherein R⁸ has another definition by performing functional grouptransformations familiar to those skilled in the art.

With reference to Scheme 12 below, the intermediate nitrones of formula6 can be prepared by N-oxidizing a quinoline derivative of formula 12with an appropriate oxidizing agent, such as m-chloro-peroxybenzoic acidor H₂O₂, in an appropriate solvent, such as dichloromethane.

Said N-oxidation may also be carried out on a precursor of a quinolineof formula 12.

The intermediate of formula 12 may be metabolized in vivo into compoundsof formula 1 via intermediates of formula 6. Hence, intermediates offormula 12 and 6 may act as prodrugs of compounds of formula 1. Suchprodrugs are within the scope of the present invention.

With reference to Scheme 13 below, the compound of formula 24, wherein Yis bromo, iodo or trifluoromethanesulfonyloxy, can be reacted to add anR³, R⁴ or R⁵ group (addition of R³ is illustrated) of the formula—C≡CR¹⁶, in particular a terminal alkyne such as(trimethylsilyl)acetylene, using palladium catalysis (with a palladiumreagent, such as bis(triphenylphosphine)-palladium(II) chloride) in thepresence of copper (I) salts, such as copper (I) iodide, in an aminesolvent, such as diethylamine, at a temperature ranging from 0° C. to100° C. to give a compound of formula 28 wherein R³ is an alkyne asdescribed above. Co-solvents, such as (N,N-dimethylformamide) DMF, maybe added to help solubilize the reactants. Additional methods ofeffecting such an alkyne addition are referred to in U.S. Pat. No.5,747,498.

With reference to Scheme 14 below, the compound of formula 26 can beprepared by reacting a compound of formula 25 with an intermediate offormula 27 where R¹² is H or phenyl. This reaction requires the presenceof a suitable base, such as tert-butyl lithium (when R¹²=H) or lithium2,2,6,6,-tetramethylpiperidine (when R¹²=phenyl), in an appropriatesolvent, such as THF. The —SR¹² group can be reductively removed fromthe compound of formula 26 with RANEY™ nickel or oxidatively with nitricacid or aqueous hydrogen peroxide in acetic acid.

The compounds of formula 1 and some of the intermediates described abovemay have one or more stereogenic centers in their structure. Suchstereogenic centers may be present in a R or a S configuration. Oximemoieties, such as where R³, R⁴, R⁵, R⁶ or R⁷ is —CH═NOR¹², may exist inE or Z configurations.

The compounds of formula 1 as prepared in the above processes aregenerally racemic mixtures of enantiomers which can be separated fromone another following resolution procedures familiar to those skilled inthe art. The racemic compounds of formula 1 may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula 1 involvesliquid chromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occurs sterospecifically.Preferably if a specific stereoisomer is desired, said compound will besynthesized by stereospecfic methods of preparation. These methods willadvantageously employ enantiomerically pure starting materials.

The compounds of formula 1 that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon evaporation of the solvent,the desired solid salt is readily obtained. The desired acid additionsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid. Cationic salts of the compounds of formula 1 are similarlyprepared except through reaction of a carboxy group with an appropriatecationic salt reagent, such as sodium, potassium, calcium, magnesium,ammonium, N,N′-dibenzylethylenediamine, N-methylglucamine (meglumine),ethanolamine, tromethamine, or diethanolamine.

The compounds of formula 1 and their pharmaceutically acceptable saltsand solvates (hereinafter referred to, collectively, as “the therapeuticcompounds”) can be administered orally, transdermally (e.g., through theuse of a patch), parenterally or topically. Oral administration ispreferred. In general, compounds of the formula 1 and theirpharmaceutically acceptable salts and solvates are most desirablyadministered in dosages ranging from about 1.0 mg up to about 500 mg perday, preferably from about 1 to about 100 mg per day in single ordivided (i.e., multiple) doses. The therapeutic compounds willordinarily be administered in daily dosages ranging from about 0.01 toabout 10 mg per kg body weight per day, in single or divided doses.Variations may occur depending on the weight and condition of the personbeing treated and the particular route of administration chosen. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effect, provided that suchlarger doses are first divided into several small doses foradministration throughout the day.

The therapeutic compounds may be administered alone or in combinationwith pharmaceutically acceptable carriers or diluents by either of thetwo routes previously indicated, and such administration may be carriedout in single or multiple doses. More particularly, the noveltherapeutic compounds of this invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, elixirs, syrups, and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, oral pharmaceutical compositions can besuitably sweetened and/or flavored.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a therapeutic compound ineither sesame or peanut oil or in aqueous propylene glycol may beemployed. The aqueous solutions should be suitably buffered if necessaryand the liquid diluent first rendered isotonic. These aqueous solutionsare suitable for intravenous injection purposes. The oily solutions aresuitable for intra-articular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art.

Additionally, it is also possible to administer the therapeuticcompounds topically and this may preferably be done by way of creams,jellies, gels, pastes, ointments and the like, in accordance withstandard pharmaceutical practice.

The therapeutic compounds may also be administered to a mammal otherthan a human. The dosage to be administered to a mammal will depend onthe animal species and the disease or disorder being treated. Thetherapeutic compounds may be administered to animals in the form of acapsule, bolus, tablet or liquid drench. The therapeutic compounds mayalso be administered to animals by injection or as an implant. Suchformulations are prepared in a conventional manner in accordance withstandard veterinary practice. As an alternative the therapeuticcompounds may be administered with the animal feedstuff and for thispurpose a concentrated feed additive or premix may be prepared formixing with the normal animal feed.

The compounds of formula 1 exhibit activity as Ras farnesylationinhibitors and are useful in the treatment of cancer and the inhibitionof abnormal cell growth in mammals, including humans. The activity ofthe compounds of formula 1 as Ras farnesylation inhibitors may bedetermined by their ability, relative to a control, to inhibit Rasfarnesyl transferase in vitro. This procedure is described below.

A crude preparation of human farnesyl transferase (FTase) comprising thecytosolic fraction of homogenized brain tissue is used for screeningcompounds in a 96-well assay format. The cytosolic fraction is preparedby homogenizing approx. 40 grams fresh tissue in 100 ml ofsucrose/MgCl₂/EDTA buffer (using a Dounce homogenizer; 10-15 strokes),centrifuging the homogenates at 1000 grams for 10 minutes at 4G,re-centrifuging the supernatant at 17,000 grams for 15 minutes at 4G,and then collecting the resulting supernatant. This supernatant isdiluted to contain a final concentration of 50 mM Tris HCl (pH 7.5), 5mN DTT, 0.2 M KCl, 20 mM ZnCl₂, 1 mM PMSF and recentrifuged at 178,000grams for 90 minutes at 4G. The supernatant, termed “crude FTase” wasassayed for protein concentration, aliquoted, and stored at −70° C.

The assay used to measure in vitro inhibition of human FTase is amodification of the method described by Amersham LifeScience for usingtheir Farnesyl transferase (3H) Scintillation Proximity Assay (SPA) kit(TRKQ 7010). FTase enzyme activity is determined in a volume of 100 mlcontaining 50 mM N-(2-hydroxy ethyl) piperazine-N-2-ethane sulfonicacid) (HEPES), pH 7.5, 30 mM MgCl₂, 20 uM KCl, 5 mM Na₂HPO₄, 5 mMdithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO),20 mg of crude FTase, 0.12 mM [3H]-farnesyl pyrophosphate ([3H]-FPP;36000 dpm/pmole, Amersham LifeScience), and 0.2 mM of biotinylated Raspeptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at itsalpha amino group and was synthesized and purified by HPLC in house. Thereaction is initiated by addition of the enzyme and terminated byaddition of EDTA (supplied as the STOP reagent in kit TRKQ 7010)following a 45 minute incubation at 37° C. Prenylated and unprenylatedBt-KTKCVIS is captured by adding 10 ml of steptavidin-coated SPA beads(TRKQ 7010) per well and incubating the reaction mixture for 30 minutesat room temperature. The amount of radioactivity bound to the SPA beadsis determined using a MicroBeta 1450 plate counter. Under these assayconditions, the enzyme activity is linear with respect to theconcentrations of the prenyl group acceptor, Bt-KTKCVIS, and crudeFTase, but saturating with respect to the prenyl donor, FPP. The assayreaction time is also in the linear range.

The test compounds are routinely dissolved in 100% dimethyl sulfoxide(DMSO). Inhibition of farnesyl transferase activity is determined bycalculating percent incorporation of tritiated-farnesyl in the presenceof the test compound vs. its incorporation in control wells (absence ofinhibitor). IC₅₀ values, that is, the concentration required to producehalf maximal farnesylation of Bt-KTKCVIS, is determined from thedose-responses obtained.

The following Examples further illustrate the invention. In thefollowing Examples, “Et” refers to ethyl, “Me” refers to methyl, and“Ac” refers to acetyl.

EXAMPLE 16-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2one

1A.5-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazole

2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (38.7 g, 127 mMol)was suspended in 190 mL of methanol (MeOH) under an atmosphere of dryN₂. To this solution was added (3-iodophenyl)acetonitrile (46.3 g, 190mMol) and 25.4 (625 mMol) of sodium hydroxide (NaOH). The solution wasthen heated to reflux and reacted at this temperature for 2 hours. Thereaction mixture was cooled to ambient temperature and the MeOH wasremoved under vacuum. The resulting red oil was partitioned betweendichloromethane (DCM) and 0.1 N aqueous NaOH. The DCM layer was washedsuccessively with 0.1 N aqueous NaOH and then brine. The DCM layer wasdried over MgSO₄, filtered and concentrated under vacuum to give a darkred oil. The oil was stirred in MeOH and the titled compoundprecipitated out as a yellow solid. The yellow solid was washed withMeOH and dried under vacuum to give 52.4 g of the titled compound whichwas used without further purification.

1B.[6-Amino-3-(4chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methanone

5-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazole(65.4 g, 130 mMol) was dissolved in a solution of tetrahydrofuran (THF)(500 mL) and DCM (100 mL). To this solution, was added 500 mL oftitanium(III) chloride (10 wt. % solution in 20-30 wt. % hydrochloricacid (HCl)) and the reaction mixture was stirred for 1 hour. Anadditional 100 mL of titanium(III) chloride (10 wt. % solution in 20-30wt. % HCl) was added to the reaction mixture and the reaction mixturewas stirred for 2.5 hours. The reaction mixture was then poured into icewater and the resulting heterogeneous solution was extracted with DCM.The DCM layer was successively washed with aqueous saturated NaHCO₃ andbrine. The DCM layer was dried over MgSO₄, filtered and concentratedunder vacuum to give titled compound as an orange oil (60 g). The oilwas used without further purification.

1C. 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one

[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one(60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under anatmosphere of dry N₂. To this solution was added 180 mL of triethylamine(NEt₃), 50 mL of acetic anhydride (Ac₂O) and 1.60 g (13.0 mMol) of4-dimethylaminopyridine (DMAP). The reaction mixture was then heated toreflux and stirred at this temperature for 20 hours. The reactionmixture was cooled to ambient temperature and the precipitate wascollected via suction filtration. The solid was washed with ethyl ether(Et₂O) and dried under vacuum to give of the titled compound (63 g)which was used without further purification.

1D. 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one

6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (63 g, 130mMol) was dissolved in THF (500 mL) under an atmosphere of dry N₂. Tothis solution, was added a 10 N aqueous NaOH (550 mL),benzyltriethylammonium chloride (13.8 g, 60.5 mMol) and methyl iodide(13.5 mL, 212.0 mMol). The reaction mixture was stirred at ambienttemperature for 15 hours after which time it was partitioned between DCMand water. The DCM layer was successively washed with water (4 times)and then brine. The organic layer was dried over MgSO₄, filtered andconcentrated under vacuum to give 51.2 g of a yellow solid as the titledcompound which was used without further purification.

1E.6-(4-Chloro-benzoyl)-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (9.98g, 20.0 mMol) was suspended in diethylamine (300 mL). To this solutionwas added 50 mL of anhydrous N,N-dimethylformamide (DMF),(trimethylsilyl)acetylene (8.5 mL) andbis(triphenylphosphine)-palladium(II) chloride (1.40 g, 2.00 mMol). Theflask was covered with aluminum foil and then copper(I) iodide (780 mg,4.09 mMol) was added causing the reaction mixture to exotherm. Afterstirring overnight under an atmosphere of dry N₂ at ambient temperature,the reaction mixture was concentrated under vacuum and the residue waschromatographed on flash silica gel eluting with a gradient of DCM toMeOH/DCM (2:98) to give 8.55 g of the titled product as a solid.

1F.6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved inanhydrous THF (200 mL) under an atmosphere of dry N₂. The solution wascooled to −78° C. and a solution of tert-butyl lithium (1.7 M inpentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0°C. After a yellow precipitate formed, the solution was cooled to −78° C.and a solution of 6-(4chloro-benzoyl)-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF(25 mL) was added. After 30 minutes, the solution was warmed to 0° C.and stirred at this temperature for 1 hour. The reaction mixture wasthen warmed to ambient temperature and stirred overnight. The reactionwas quenched with 20 mL of saturated aqueous ammonium chloride (NH₄Cl)and then partitioned between DCM and water. The DCM layer was dried oversodium sulfate (Na₂SO₄), filtered and concentrated under vacuum. Theresidue was chromatographed on flash silica gel eluting with a gradientfrom DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as asolid.

1G.6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(5.0 g, 8.6 mMol) was dissolved in ethanol (40 mL) to which was addedRaney™ nickel (ca. 10 g) and the reaction was heated to reflux. MoreRANEY™ nickel was added every 20 minutes until mass spectral analysis ofthe reaction showed that the starting material had been consumed. Thereaction mixture was cooled to ambient temperature and filtered throughCELITE™ (diatomaceous earth). The CELITE™ was washed with copiousamounts of ethanol. The filtrates were combined and concentrated undervacuum to give 3.88 g of the titled compound.

C.I. m/z 552 [M+1]; ¹H NMR (CD₃OD) δ7.64-7.75 (m, 3H), 7.17-7.48 (m, 9H), 6.59 (s, 1 H), 6.17 (s, 1 H), 3.79 (s, 3 H), 3.42 (s, 3 H), 0.23 (s,9 H).

EXAMPLE 26-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3ethynyl-phenyl)-1-methyl-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl)]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(3.88 g, 7.03 mMol) was dissolved in THF (10 mL) under an atmosphere ofdry N₂. To this solution was added a solution of 1.0 Ntetrabutylammonium fluoride in THF (20 mL, 20 mMol). The reactionmixture was stirred overnight at ambient temperature and was thenconcentrated under vacuum. The residue was partitioned between4-(dicyanomethylene)-2-methyl-(4-dimethylamino-styryl)-4H-pyran (DCM)and water. The DCM layer was saved and washed 3 more times with waterand then with brine. The DCM layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was chromatographed on flashsilica gel eluting with a gradient from DCM to MeOH/DCM (4:96) to give3.01 g of the titled compound.

C.I. m/z 480 [M+1]; ¹H NMR (CD₃OD) δ7.75 (dd, J=2.1, 8.9 Hz, 1H), 7.69(s, 1 H), 7.66 (d, 8.5 Hz, 1 H), 7.52 (d, J=7.9 Hz, 1 H), 7.41 (t, J=7.7Hz, 1 H), 7.38 (s, 1 H), 7.29 (m, 3 H), 7.23 (d, J=1.7 Hz, 1 H), 7.17(d, J=8.5 Hz, 2 H), 6.59 (s, 1 H), 6.16 (s, 1 H), 3.79 (s, 3 H), 3.60(s, 1 H), 3.42 (s, 3 H).

Separation of the Enantiomers of6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(4.96 g) was separated into its enantiomers and purified byhigh-performance liquid chromatography over CHIRALPAK™ AD (manufacturedby Daicel Chemical Industries, LTD, Osaka, Japan) (20 μm; eluent:Hexane/isopropanol/diethylamine 85/15/0.1; 30° C.). Under theseconditions, 1.73 g of the faster eluting enantiomer A ({α}_(D) ²⁰=−25.1(c=50.0 mg/5 mL)) was obtained and 2.07 g of the slower movingenantiomer B ({α}_(D) ²⁰=+24.2 (c=27.7 mg/5 mL)). Both enantiomerswere >97% optically pure.

EXAMPLE 3

6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one(1.75 mg, 3.65 mMol) was dissolved in 5.0 mL of thionyl chloride (SOCl₂)and stirred at room temperature under an atmosphere of dry N₂ for 2hours. The reaction mixture was then concentrated under reduced pressureand the resulting solid was taken up in toluene and concentrated undervacuum. The resulting solid was dissolved in THF (15 mL) and to thismixture was added concentrated ammonium hydroxide (20 mL). The reactionmixture was stirred at ambient temperature for 1 hour and was thenpartitioned between DCM and 1.0 N aqueous NaOH. The aqueous layer wasextracted again with DCM and the organic layers were then combined,dried over Na₂SO₄, filtered and concentrated under vacuum to give abrown solid. The residue was chromatographed on flash silica gel elutingwith a gradient from MeOH/ethyl acetate (EtOAc)/ ammonium hydroxide(NH₄OH) (5:95:0.1) to MeOH/EtOAc/NH₄OH (10:90:0.1) to give 643 mg of thetitled compound.

C.I. m/z 479 [M+1]; ¹H NMR (CD₃OD) δ7.84 (dd, J=2.3, 9.1 Hz, 1H), 7.70(d, 8.9 Hz, 1 H), 7.57 (s, 1 H), 7.51 (m, 1 H), 7.37 (t, J=7.7 Hz, 1 H),7.33 (s, 1 H), 7.28 (m, 2 H), 7.21 (dd, J=1.0, 7.7 Hz, 1 H), 7.10 (d,J=8.5 Hz, 2 H), 6.96 (d, J=1.3 Hz, 1 H), 6.57 (s, 1 H), 6.10 (s, 1 H),3.78 (s, 3 H), 3.60 (s, 1 H), 3.41 (s, 3 H).

Separation of the Enantiomers of6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one

6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2one(5.25g) was separated into its enantiomers and purified byhigh-performance liquid chromatography over CHIRALCEL™ OD (manufacturedby Daicel Chemical Industries, LTD, Osaka, Japan) (20 μm; eluent:Hexane/isopropanol/diethylamine 6713310.1; 25° C.). Under theseconditions, 2.29 g of the faster eluting enantiomer A was obtained and1.60 g of the slower moving enantiomer B. Both enantiomers were >97%optically pure.

EXAMPLE 46-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-[3-(3-methyl-but-1-ynyl)-phenyl]-1H-quinolin-2-one

The same procedure was used as described in example 1 except that3-methyl-1-butyne was used in the place of (trimethylsilyl)acetylene instep 1E to give the titled compound.

C.I. m/z 522 [M+1]; ¹H NMR (CDCl₃) δ7.60 (m, 2 H), 7.42 (d, J=7.9 Hz, 1H), 7.37 (d, J=7.9 Hz, 1 H), 7.25-7.29 (m, 5 H), 7.17 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.1 Hz 1 H), 6.60 (s, 1 H), 6.31 (brs, 1 H), 3.70 (s, 3H), 3.43 (s, 3 H), 2.79 (m, J=6.9 Hz, 1 H), 1.26 (d, J=6.9 Hz, 6 H).

EXAMPLE 56-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one

The same procedure was used as described in example 1 except that3,3-dimethyl-1-butyne was used in the place of (trimethylsilyl)acetylenein step 1E to give the titled compound.

C.I. m/z 536 [M+1]; ¹H NMR (CDCl₃) δ7.84 (brs, 1 H), 7.60 (m, 1 H), 7.40(m, 3 H), 7.21-7.27 (m, 4 H), 7.15 (d, J=8.5 Hz, 2 H), 7.02 (d, J=7.3Hz, 1 H), 6.61 (s, 1 H), 6.34 (brs, 1 H), 3.70 (s, 3 H), 3.48 (s, 3 H),1.30 (s, 9 H).

EXAMPLE 66-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-[3-(4-methyl-pent-1-ynyl)-phenyl]-1H-quinolin-2-one

The same procedure was used as described in example 1 except that4-methyl-1-pentyne was used in the place of (trimethylsilyl)acetylene instep 1E to give the titled compound.

C.I. m/z 536 [M+1]; ¹H NMR (CDCl₃) δ7.84 (brs, 1 H), 7.62 (d, J=8.1 Hz,1 H), 7.39-7.44 (m, 2 H), 7.25-7.30 (m, 5 H), 7.17 (d, J=8.3 Hz, 2 H),7.05 (d, J=7.2 Hz, 1 H), 6.63 (s, 1 H), 6.36 (brs, 1 H), 3.72 (s, 3 H),3.49 (s, 3 H), 2.31 (d, J=6.4 Hz, 2 H), 1.91 (m, 1 H), 1.03 (d, J=6.6Hz, 6 H).

EXAMPLE 76-[(4-Chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,4]triazol-1-yl-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one

6[(4chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one(330 mg, 0.633 mMol) was dissolved in 4 mL of thionyl chloride andstirred at ambient temperature under a stream of dry N₂ for 2 hours. Thereaction mixture was then concentrated under vacuum and toluene (5 mL)was added to the reaction mixture which was subsequently concentratedunder vacuum to give a yellow solid. 210 mg of the yellow solid wasdissolved in 5.0 mL of anhydrous DMF under an atmosphere of dry N₂. Tothis solution was added 800 mg of potassium carbonate and 300 mg of1,2,4-triazole and the reaction mixture was subsequently heated to 80°C. and stirred overnight at this temperature. The reaction mixture wasthen concentrated under vacuum and partitioned between EtOAc and water.The EtOAc layer was washed 3 more times with water and then with brine.The EtOAc layer was then dried over Na₂SO₄, filtered and concentratedunder vacuum to give a yellow solid. The solid was chromatographed onflash silica gel eluting with a gradient of MeOH/DCM/NH₄OH (2/9810.1) toMeOH/DCM/NH₄OH (7/93/0.1) to give 150 mg of the titled product as awhite solid.

¹H NMR (CDCl₃) δ8.06 (s, 1 H), 7.89 (s, 1 H), 7.59 (brs, 1 H), 7.41 (d,J=8.7 Hz, 2 H), 1 H), 7.22-7.27 (m, 5 H), 7.00-7.05 (m, 2 H), 6.89 (d,J=8.7 Hz, 2 H), 6.67 (s, 1 H), 6.54 (brs, 1 H), 3.75 (s, 3 H), 3.08 (s,3 H), 1.31 (s, 9 H).

EXAMPLE 86-[(4-Chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,4]triazol-1-yl-methyl]-1-methyl-4-[3-(3-methyl-but-1-ynyl)-phenyl]-1H-quinolin-2-one

The same procedure was used as described in example 7 except that6-[(4chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-[3-(3-methyl-but-1-ynyl)-phenyl]-1H-quinolin-2-onewas used in the place of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-oneto give the titled compound.

¹H NMR (CDCl₃) δ8.06 (s, 1 H), 7.90 (s, 1 H), 7.43-7.48 (m, 2H),7.20-7.34 (m, 6 H), 7.01 (d, J=8.1 Hz, 1 H), 6.98 (s, 1 H), 6.79 (m,3 H), 6.70 (s, 1 H), 3.77 (s, 3H), 3.28 (s, 3 H), 2.80 (m, 1 H), 1.26(d, J=6.9 Hz, 6 H).

EXAMPLE 96-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol4-yl)-methyl]-4-(3-ethynyl-4-fluoro-phenyl)-1-methyl-1H-quinolin-2-one

9A. 4-Bromomethyl-1-fluoro-2-iodo-benzene

4-Fluoro-3-iodotoluene (50 g, 210 mMol), N-bromosuccinimide (37.7 g, 212mMol) and 2,2′-azobis-(2-methylpropionitrile) (348 mg, 2.12 mMol) weredissolved in carbon tetrachloride (300 mL) under an atmosphere of dryN₂. The mixture was heated to reflux for 4 hours and then cooled toambient temperature. The mixture was concentrated under vacuum andtriturated with Et₂O. The filtrate was successively washed with water,aqueous saturated NaHCO₃ and brine. The ether layer was dried overMgSO₄, filtered and concentrated under vacuum to give a red oil. The oilwas chromatographed on flash silica gel eluting with hexanes to give33.8 g of the titled compound as a white solid.

9B. (4-Fluoro-3-iodo-phenyl)-acetonitrile

4-Bromomethyl-1-fluoro-2-iodo-benzene (33.8 g, 107 mMol) was added to240 mL of a 0.5 M solution of lithium cyanide in DMF. The reactionmixture was heated to 80° C. under an atmosphere of dry N₂ and stirredovernight at this temperature. The mixture was then cooled to ambienttemperature and partitioned between Et₂O and 0.1 N aqueous NaOH. TheEt₂O layer was then washed 4 more times with 0.1 N aqueous NaOH. TheEt₂O layer was then dried over MgSO₄, filtered and concentrated undervacuum to give 24.7 g of the titled compound as a red solid which wasused without purification.

9C.6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-4-fluoro-phenyl)-1-methyl-1H-quinolin-2-one

The procedure was used as that of examples 1 and 2 except that(4-fluoro-3-iodophenyl)acetonitrile was used in the place of(3-iodophenyl)acetonitrile in step 1A to give the titled compound.

C.I. m/z 498 [M+1]; ¹H NMR (CDCl₃) δ7.61 (d, J=8.1 Hz, 1H), 7.53 (brs, 1H), 7.36 (d, 9.0 Hz, 1 H), 7.04-7.33 (m, 8 H), 6.52 (s, 1 H), 6.21 (brs,1 H), 3.67 (s, 3 H), 3.38 (s, 3 H), 3.36 (s, 1 H).

EXAMPLE 106-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-phenylethynyl-phenyl)-1H-quinolin-2-one

The procedure was used as that of example 1 except that phenylacetylenewas used in the place (trimethylsilyl)acetylene in step 1E to give thetitled compound.

C.I. m/z 556 [M+1]; ¹H NMR (CDCl₃) δ7.60 (dd, J=2.1, 8.8 Hz, 1H), 7.50(m, 3 H), 7.43 (brs, 1 H), 7.21-7.37 (m, 9 H), 7.17 (d, J=8.5 Hz, 2 H),7.08 (d, J=7.5 Hz, 1 H), 6.61 (s, 1 H), 6.26 (brs, 1 H), 3.69 (s, 3 H),3.38 (s, 3 H).

EXAMPLE 116-[(4-Chloro-phenyl-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]4-[3-(4-hydroxy-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one

11A.6-(4-Chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-one

6-(4-Chloro-benzoyl)4-[3-(4-hydroxy-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one(1.41 g, 3.20 mMol), which was prepared by substituting 3-butyn-1-ol for(trimethylsilyl)acetylene in step 1E of example 1, and triethylamine(900 mL, 6.40 mMol) were dissolved in DCM (15 mL) under an atmosphere ofdry N₂. To this solution was added triphenylmethyl chloride (980 mg,3.50 mMol) and the mixture was stirred at ambient temperature for 4hours. The reaction mixture was then partitioned between Et₂O/EtOAc andwater. The organic layer was washed again with water and then withsaturated aqueous NaHCO₃, dried over MgSO₄, filtered and concentratedunder vacuum to give a white foam as the titled compound which was usedwithout further purification.

11B.6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(4-hydroxy-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one

2-Mercapto-1-methylimidazole (400 mg, 3.50 mMol) was dissolved inanhydrous THF (7.0 mL) under a stream of dry N₂. The solution was thencooled to −78° C. and a solution of 2.8 mL of a 2.5 M solution ofn-butyllithium in hexanes was then added. After the addition wascomplete, the reaction mixture was warmed to ambient temperature andstirred at this temperature for 1 hour. The reaction mixture was thencooled to −78° C. and a solution of(4-chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-onein THF (7.0 mL) was added to the mixture. The reaction was warmed toambient temperature and stirred overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl (25 mL) and partitioned betweenDCM and water. The DCM layer was dried over Na₂SO₄, filtered andconcentrated under vacuum to give a green solid. The green solid wasdissolved in 30 mL of acetic acid (AcOH) and the solution was cooled toabout 5° C. To this solution was added 2.0 mL of 30% aqueous hydrogenperoxide (H₂O₂) dropwise. After the addition was complete, the reactionmixture was stirred at ambient temperature for 30 minutes. The reactionmixture was then cooled to 0° C., 200 mL of water was added and thereaction was basified to pH=10 with the slow addition of NaOH. Sodiumsulfite was added portionwise until testing with starch-iodine papershowed no H₂O₂ left. The reaction mixture was partitioned between DCMand water. The DCM layer was dried over Na₂SO₄, filtered andconcentrated under vacuum to give a green solid. The green solid wasdissolved in a solution of MeOH/DCM (25:3) to which was added 3 Naqueous HCl (3.0 mL). The solution was then heated to 68° C. and reactedat this temperature for 2 hours. The solution was concentrated undervacuum to a thick sludge and then was partitioned between DCM and 0.01 Naqueous NaOH. The DCM layer was concentrated under vacuum andchromatographed on flash silica gel eluting with a gradient ofMeOH/EtOAc/NH₄OH (5:95:.01) to MeOH/EtOAc/NH₄OH (10:90:.01) to give thetitled compound.

C.I. m/z 524 [M+1]; ¹H NMR (CDCl₃) δ7.53 (m, 1 H), 7.43 (brs, 1 H), 7.34(d, J=7.9 Hz, 1 H), 7.16-7.26 (m, 8 H), 7.03 (d, J=7.5 Hz, 1 H), 6.38(s, 1 H), 6.28 (s, 1 H), 3.73 (m, 2 H), 3.52 (s, 3 H), 2.39 (s, 3 H),2.61 (m, 2 H).

EXAMPLE 126-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one

12A.6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one

A solution of 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one(9.68 g, 19.9 mmol), prepared as described in PCT international patentapplication publication number WO 97/21701 (published Jun. 19, 1997)(3.10 g, 7.87 mmol) in DMF (70 mL) was treated with cesium carbonate(23.1 g, 19.9 mmol) and (bromomethyl)cyclopropane (5.37 g, 39.8 mmol).The reaction mixture was stirred at room temperature for 12 hours,diluted with dichloromethane (75 mL), and washed with 1N HCl (2×50 mL)and brine (100 mL). The combined organic extracts were dried (MgSO₄),filtered, and concentrated in vacuo to give a black residue.Purification by flash column chromatography (silica, ethylacetate:petroleum ether 1:9-3:7) gave6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one(6.79 g, 63%) as a yellow solid.

C.I. m/z 540 [M+1]; ¹H NMR (CDCl₃): δ=8.05 (dd, J=9.0, 2.0 Hz, 1H), 7.92(d, J=2.0 Hz, 1H), 7.80-7.77 (m, 2H), 7.71-7.64 (m, 3H), 7.50-7.46 (m,2H), 7.37(dd, J=7.8. 1.2 Hz, 1H), 7.22-7.17 (m, 1H), 6.68 (s, 1H), 4.32(d, J=6.8 Hz, 2H), 1.34-1.23 (m, 1H), 0.64-0.56 (m, 4H).

12B.6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one

A solution of6-(4-chloro-benzoyl)-1-cyclopropylmethyl-4-3-iodo-phenyl)-1H-quinolin-2-one(4.0 g, 7.41 mmol) in DMF/diethylamine (1:1, 80 mL) was treated withpalladium (II) bis(triphenyl)phosphine chloride (0.26 g, 0.37 mmol),trimethylsilylacetylene (1.09 g, 11.1 mmol), and copper (I) iodide (0.21g, 1.09 mmol). The reaction mixture was stirred at room temperature for3 hours, concentrated in vacuo, poured into H₂O (450 mL), and filteredto give a crude brown foam. Purification by flash column chromatography(silica, ether:petroleum ether 1:1) gave6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(3.47 g, 92%) as a yellow solid.

C.I. m/z 510 [M+1]; ¹H NMR (CDCl₃): δ=8.08 (dd, J=8.9, 1.9 Hz, 1H), 7.92(d, J=1.7 Hz, 1H), 7.72-7.65 (m, 3H), 7.58-7.29 (m, 6H), 6.69 (s, 1H),4.33 (d, J=7.1 Hz, 2H), 1.34-1.25 (m,1H), 0.63-0.55 (m, 4H), 0.26 (s,9H).

12C.6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one

A solution of 2-(tert-butyl-dimethyl-silanyl)-1-methyl-1H-imidazole(1.71 g, 8.7 mmol) in THF (40 mL) at −78° C. was treated withsec-butyllithium (1.3 M in cyclohexane, 8.4 mL, 10.9 mmol). The reactionmixture was warmed to 0° C., stirred for 3 hours, and cooled to −78° C.A solution of6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(3.47 g, 6.8 mmol) (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated intothe reaction mixture, slowly warmed to room temperature, and stirredovernight. The reaction mixture was quenched with ammonium chloride (12mL), diluted with ether (200 mL), and washed with H₂O (200 mL) and brine(200 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo to give6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2one(4.50 g) as a yellow foam. The crude material was used in the next stepwithout any further purification.

A solution of6-[[2-(tert-Butyldimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4chloro-phenyl)-hydroxy-methyl-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one(4.50 g crude) in THF (100 mL) was treated with tetrabutylammoniumchloride (1 M in THF, 10.0 mmol). The reaction mixture was stirred atroom temperature for 12 hours, poured into H₂O (200 mL), and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith 1N HCl (100 mL), aqueous NaHCO₃ (100 mL), and brine (100 mL), dried(MgSO₄), filtered, and concentrated in vacuo to give a light green foam.Purification by flash column chromatography (silica, EtOAc:pet.ether:NH₄OH 1:1:0.01) gave6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one(1.82 g, 51%) as a yellow powder.

C.I. m/z 520 [M+1]; ¹H NMR (CDCl₃): δ=7.59 (dd, J=9.1, 2.1 Hz, 1H),7.53-7.51 (m, 2H), 7.35-7.25 (m, 6H), 7.18-7.15 (m, 3H), 6.60 (s, 1H),6.30 (s, 1H), 4.25 (d, J=7.1 Hz, 2H), 3.37 (s, 3H), 3.13 (s, 1H), 1.76(br.s, 1H), 1.39-1.25 (m, 1H), 0.59-0.51 (m, 4H).

Separation of the Enantiomers of6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3ethynyl-phenyl)-1H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one(1.02 g) was separated into its enantiomers and purified byhigh-performance liquid chromatography over CHIRALCEL™ OD (manufacturedby Daicel Chemical Industries, LTD, Osaka, Japan) (20 μm; eluent:hexane/isopropanol/diethylamine 65/35/0.1; 25° C.). Under theseconditions, 0.42 g of the faster eluting enantiomer A was obtained and0.43 g of the slower eluting enantiomer B. Both enantiomers were >97%optically pure.

EXAMPLE 136-[Amino-(4chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one

The same procedure that was used in example 3 was followed except6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one(1.80 g, 3.5 mmol) was used in place of6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-oneto give6-[Amino(4chloro-phenyl)-(3-methyl-3H-imidazol-4-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one(1.12 g, 62%) as a yellow foam.

C.I. m/z 519 [M+1]; ¹H NMR (CDCl₃): δ=7.57-7.51 (m, 3H), 7.43 (s, 1H),7.36-7.31 (m, 2H), 7.26-7.22 (m, 2H), 7.18 (d, J=7.7 Hz, 1H), 7.09-7.05(m, 3H), 6.63 (s, 1H), 6.32 (s, 1H), 4.28 (d, J=7.1 Hz, 2H), 3.39 (s,3H), 3.13 (s, 1H), 2.11 (br.s, 2H), 1.31-1.27 (m, 1H), 0.61-0.52 (m,4H).

EXAMPLE 146-[(4-Chloro-phenyl)-(3-methyl-3H-imidazol-4yl)-[1,2,4]triazol-1-yl-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2one

The same procedure that was used in example 7 was followed except6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-onewas used in place of6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-oneto give6-[(4-Chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,4]triazol-1-yl-methyl)-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2one(21.0 mg, 55%) as a yellow film.

C.I. m/z 571 [M+1]; ¹H NMR (CDCl₃): δ=8.06 (s, 1H), 7.89 (s, 1H),7.56-7.52 (m, 3H), 7.34-7.25 (m, 5H), 7.14 (dd, J=7.8, 1.4 Hz, 1H), 7.04(d, J=2.1 Hz, 1H), 6.95-6.91 (m, 2H), 6.66 (s, 1H), 6.55 (s, 1H), 4.26(d, J=6.9 Hz, 2H), 3.14 (s, 1H), 3.06 (s, 3H), 1.30-1.23 (m, 1H),0.61-0.52 (m, 4H); IR: v_(max)=3500, 1650, 1500, 1325, 1275, 1125, 1100,1025 cm⁻¹.

What is claimed is:
 1. A pharmaceutical composition for the treatment ofcancer or benign proliferative disease in a mammal which comprises anamount of a compound of formula 1

or a pharmaceutically acceptable salt, prodrug or solvate thereofwherein: the dashed line indicates that the bond between C-3 and C-4 ofthe quinolin-2-one ring is a single or double bond; R¹ is selected fromH, C₁-C₁₀ alkyl, —(CR¹³R¹⁴)_(q)C(O)R¹², —(CR¹³R¹⁴)_(q)C(O)OR¹⁵,—(CR¹³R¹⁴)_(q)OR¹², —(CR¹³R¹⁴)_(q)SO₂R¹⁵,—(CR¹³R¹⁴)_(t)(C₃-C₁₀cycloalkyl), —(CR¹³R¹⁴)_(t)(C₆-C₁₀aryl), and—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl andheterocyclic R¹ groups are optionally fused to a C₆-C₁₀ aryl group, aC₅-C₈ saturated cyclic group, or a 4-10 membered heterocyclic group; andthe foregoing R¹ groups, except H but including any optional fused ringsreferred to above, are optionally substituted by 1 to 4 R⁶ groups; R² ishalo, cyano, —C(O)OR¹⁵, or a group selected from the substituentsprovided in the definition of R¹²; each R³, R⁴, R⁵, R⁶, and R⁷ isindependently selected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, halo,cyano, intro, trifluoromethyl, trifluoromethoxy, azido, —OR¹², —C(O)R¹²,—C(O)OR¹², —NR¹³C(O)OR¹⁵, —OC(O)R¹², —NR¹³SO₂R¹⁵, —SO₂NR¹²R¹³,—NR¹³C(O)R¹², —C(O)NR¹²R¹³, —NR¹²R¹³, —CH═NOR¹², —S(O)_(j)R¹² wherein jis an integer from 0 to 2, —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl),—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), —(CR¹³R¹⁴)_(t)(C₃-C₁₀cycloalkyl), and —(CR¹³R¹⁴)_(t)C≡CR¹⁶, and wherein in the foregoing R³,R⁴, R⁵, R⁶, and R⁷ groups t is an integer from 0 to 5; the cycloalkyl,aryl and heterocyclic moieties of the foregoing groups are optionallyfused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclic group, or a 4-10membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryland heterocyclic groups are optionally substituted by 1 to 3substituents independently selected from halo, cyano, intro,trifluoromethyl, trifluoromethoxy, azido, —NR¹³SO₂R¹⁵, —SO₂NR¹²R¹³,—C(O)R¹², —C(O)OR¹², —OC(O)R¹², —NR¹³C(O)OR¹⁵, —NR¹³C(O)R¹²,—C(O)NR¹²R¹³, —NR¹²R¹³, —OR¹², C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), and —(CR¹³R¹⁴)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5; R⁸ is H, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, cyano, —C(O)OR¹³, —SR¹², —(CR¹³R¹⁴)_(t)(4-10membered heterocyclic), wherein t is an integer from 0 to 5, orC₁-C₆alkyl, wherein said heterocyclic and alkyl moieties are optionallysubstituted by 1 to 3 R⁶ substituents; R⁹ is —(CR¹³R¹⁴)_(t)(imidazolyl)wherein t is an integer from 0 to 5 and said imidazolyl moiety isoptionally substituted by 1 or 2 R⁶ substituents; each R¹⁰ and R¹¹ isindependently selected from the substituents provided in the definitionof R⁶; each R¹² is independently selected from H, C₁-C₁₀ alkyl,—(CR¹³R¹⁴)_(t)(C₃-C₁₀ cycloalkyl), —(CR¹³R¹⁴)_(t)(C₆-C₁₀ aryl), and—(CR¹³R¹⁴)_(t)(4-10 membered heterocyclic), wherein t is an integer from0 to 5; said cycloalkyl, aryl and heterocyclic R¹² groups are optionallyfused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclic group, or a 4-10membered heterocyclic group; and the foregoing R¹² substituents, exceptH, are optionally substituted by 1 to 3 substituents independentlyselected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,azido, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —NR¹³C(O)R¹⁴, —C(O)NR¹³R¹⁴,—NR¹³R¹⁴, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; each R¹³ and R¹⁴ isindependently H or C₁-C₆ alkyl, and where R¹³ and R¹⁴ are as or(CR¹³R¹⁴)_(t) each is independently defined for each iteration of q ortin excess of 1; R¹⁵ is selected from the substituents provided in thedefinition of R¹² except R¹⁵ is not H; R¹⁶ is selected from the list ofsubstituents provided in the definition of R¹² and —SiR¹⁷R¹⁸R¹⁹; R¹⁷,R¹⁸ and R¹⁹ are each independently selected from the substituentsprovided in the definition of R¹² except R¹⁷, R¹⁸ and R¹⁹ are not H; andprovided that at least one of R³, R⁴ and R⁵ is —(CR¹³R¹⁴)_(t)C≡CR¹⁶wherein t is an integer from 0 to 5 and R¹³, R¹⁴, and R¹⁶ are as definedabove, that is effective in inhibiting farnesyl protein transferase anda pharmaceutically acceptable carrier.